Temporal Trends in End-Tidal Capnography and Outcomes in Out-of-Hospital Cardiac Arrest

Key Points Question Is there an association between end-tidal capnography changes over resuscitation and outcomes from out-of-hospital cardiac arrest? Findings In this secondary analysis of 1113 patients in the Pragmatic Airway Resuscitation Trial, temporal increases in end-tidal capnography over resuscitation were associated with return-of-spontaneous circulation in out-of-hospital cardiac arrest. Meaning These results suggest the importance of dynamic time-varying end-tidal capnography, which may be leveraged by clinicians in guiding resuscitation decisions.


Introduction
2][3] Despite decades of research in out-of-hospital cardiac arrest (OHCA), survival has remained low. 1 To improve survival, both the International Liaison Committee on Resuscitation (ILCOR) and American Heart Association prehospital recommendations have emphasized the importance of 9-1-1 activation, rapid bystander cardiopulmonary resuscitation, early defibrillation, and provision of high-quality cardiopulmonary resuscitation (CPR). 4,5In addition, recent studies have highlighted the importance of high-quality ventilation for improved survival and the need for ventilation monitoring during OHCA. 6ideline recommendations encourage use of end-tidal carbon dioxide (EtCO 2 ) capnography during resuscitation from OHCA for confirmation of advanced airway placement as well as monitoring progress of resuscitation. 4,6However, the practical application of capnography for the latter goal is unclear. 7,82][13][14][15] To date, limited data has been presented to support this approach.
The dynamic variations in EtCO 2 capnometry during resuscitation and the association with outcomes remains unknown.Our objective was to determine the association between temporal trends of EtCO 2 and ROSC in the Pragmatic Airway Resuscitation Trial (PART).

Study Design, Setting, and Participants
This was a secondary analysis of EtCO 2 capnography waveforms from the PART trial. 16The PART trial enrolled adults (age Ն18 years) with nontraumatic out-of-hospital cardiac arrest from 27 emergency medical services (EMS) agencies from 5 communities of the Resuscitation Outcomes Consortium.PART, a cluster randomized trial, assigned adult OHCA to strategies of laryngeal tube insertion or endotracheal intubation airway management.Exclusion criteria consisted of patients less than 18 years of age, pregnant people, prisoners, and traumatic OHCAs.The trial enrolled patients from December 1, 2015, through November 4, 2017.Race and ethnicity in PART was reported from EMS agencies (and included the following categories: Black or African American, White, and other [American Indian or Alaska Native, Asian, Hispanic, Pacific Islander, other, and unknown]).The trial protocol is available in Supplement 1.For this post hoc analysis, we included only participants in whom an advanced airway was successfully placed and with continuous capnography data available.
The institutional review board of The Ohio State University approved this retrospective secondary analysis of the parent trial and informed consent was waived because patients had an emergent condition and were unable to consent in time for treatment (in accordance with 21 CFR 50.24).This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

JAMA Network Open | Emergency Medicine
End-Tidal Capnography Changes and Outcomes in Out-of-Hospital Cardiac Arrest

Measures
The primary measure was EtCO 2 over the course of resuscitation from initial placement through either ROSC or termination of resuscitation.EMS agencies collected continuous EtCO 2 capnography waveforms using portable cardiac defibrillator monitors as part of their advanced airway standard of care.The cardiac monitors used in this study were the LifePak 15 series (Physio-Control), the X-series (ZOLL Medical Corporation) and the MRx series (Philips Healthcare).
We identified maximal EtCO 2 values for each ventilation using previously validated automated signal processing. 17Import and analysis of capnography waveforms were accomplished using MATLAB (Mathworks) and a custom graphical user interface (GUI). 18,19The algorithm detects maximal EtCO 2 values per ventilation.We determined mean EtCO 2 in 1-minute epochs.We included all cases with greater than 50% interpretable EtCO 2 signal in at least 1 of the epochs.We also provide histogram plots of the change in capnography from initial to end of resuscitation and box plots displaying distribution of slope calculations to evaluate individualized change in capnography.

Outcomes
Our primary outcome of interest was ROSC, which was determined by clinical evaluation of palpable pulses as marked in the parent trial by EMS clinicians or physicians at the receiving emergency department.Secondary outcomes included survival to 72 hours after cardiac arrest.We also separated nonsurvivors (including those who obtained ROSC) and survivors based on clinical information marked in the parent trial by hospital physicians.

Statistical Analysis
We planned to evaluate temporal changes in EtCO 2 in relation to ROSC.We divided cases into ROSC or non-ROSC and survivors or nonsurvivors for analysis.We included the time from ROSC or cessation of resuscitation efforts defined as last chest compression and up to the previous 20 minutes of resuscitation for figure presentations.Therefore, time in this analysis is marked by negative numbers where −20 minutes would represent initial or early EtCO 2 values on EMS arrival (eAppendix 1 in Supplement 2).
We compared discrete time points between ROSC vs non-ROSC and survivors vs nonsurvivors using the Mann-Whitney test.We determined the association between temporal trends in EtCO 2 using Cochran-Armitage test of trend.The slope of EtCO 2 was calculated by change in EtCO 2 over sequential minutes available during the resuscitation (mm Hg/min).Tests were 2-sided and P < .05 was considered significant.Finally, we performed an adjusted multivariable logistic regression model for outcomes adjusted for the slope of EtCO 2 , age, sex, witnessed cardiac arrest (bystander, EMS witnessed, unwitnessed), bystander CPR (yes/no), initial ECG rhythm (shockable vs nonshockable), public location, chest compression rate (within American Heart Association [AHA] recommendations of 100-120 [yes/no]), chest compression depth (within AHA recommendations of 5-6 cm [yes/no]), successful airway placed and epinephrine given (yes/no).Chest compression fraction within AHA recommended rates (>0.6) was achieved in 99.6% of all cases so this covariate was omitted.
In a sensitivity analysis to account for potential ventilation quality effects on capnography, we repeated analysis using ventilations only within AHA recommendations of 6 to 12 breaths per minute.
As length of resuscitation time may affect modeling, we performed a stratified multivariate adjusted regression model considering less than 10 minutes resuscitation to be short resuscitation and greater than 10 minutes resuscitation to be prolonged resuscitation.We also repeated the analysis using generalized estimated equations to account for the randomized cluster trial design.We considered multicollinearity within our models using a variance inflation factor greater than 10.We assessed goodness-of-fit testing using Hosmer-Lemeshow statistics.We considered our models to have acceptable discrimination if the area under the receiver operating characteristic curve (AUC) was at least 0.70; excellent discrimination if AUC was at least 0.8, and outstanding discrimination if AUC was at least 0.9. 20Analysis was conducted using Stata version 16.0 (Stata Inc) from X to Y.

JAMA Network Open | Emergency Medicine
End-Tidal Capnography Changes and Outcomes in Out-of-Hospital Cardiac Arrest
Adjusting for Utstein variables including age, sex, public location, bystander witnessed status, bystander CPR, initial rhythm, chest compression rate, chest compression depth, and epinephrine given; the slope of EtCO 2 change over resuscitation was associated with both ROSC and survival (logistic regression P < .001)(Table 2).Discrimination for ROSC (0.78 [95% CI, 0.73-0.80])was acceptable and for survival (0.82 [95% CI, 0.77-0.85])was excellent.Goodness-of-fit testing statistics were acceptable for ROSC (0.46) and survival (0.49).As a sensitivity analysis using only AHA-recommended ventilation rates for inclusion in a multivariate-adjusted regression model, the slope of EtCO      The whisker above the box is the upper adjacent value (equal to the 75th percentile plus 1.5 times the IQR).

JAMA Network Open | Emergency Medicine
End Continuous capnography offers advantages in that it can account for waveform variability and allows for monitoring change during resuscitation. 8Through automated signal processing, 17,19,25 vital EtCO 2 information such as EtCO 2 value change and rate of change can be quickly obtained and correlated with outcomes.Similar to our findings, 2 studies found that the absence of decreasing EtCO 2 from initial to final EtCO 2 value was associated with achieving ROSC in OHCA. 11,15Our study shows the benefit in leveraging capnography over the resuscitation rather than discrete time points.
Collectively, these works encourage the use of dynamic changes in EtCO 2 capnography as a potential predictor for OHCA outcome.
Our findings may have important clinical implications.The results of this analysis highlight that there are many dimensions of EtCO 2 that may better guide resuscitation.Using the change in capnography throughout resuscitation may be an advancement over using discrete EtCO 2 cut-offs, 14 although our findings require further validation.Additional questions that remain include the duration of EtCO 2 capnography monitoring necessary to determine a reliable temporal change estimate.Naturally, this is not the only way to analyze these data.Other potential approaches include machine learning algorithms or inclusion of peak volume or thoracic compliance.These are complimentary targets for future projects.Validation of this approach (EtCO 2 trend monitoring) can be useful in resuscitation and merits independent validation prior to clinical application.

Limitations
This study has limitations.These data are a retrospective review of one-third of previously collected data from agencies involved in a clinical trial performed more than 7 years ago.Generalizability of ventilation quality metrics from potentially high-performing emergency medical services agencies may not be broadly applicable. 26,27Furthermore, the clinical trial evaluated the effectiveness of airway device on OHCA outcomes.We attempted to adjust for interventions such as airway choice, ventilation quality, chest compression quality, and epinephrine given.However, we are unable to adjust for defibrillation timing, cumulative dosing of epinephrine or other medications such as sodium bicarbonate as it is not available or underpowered in this initial dataset.We also are unable to evaluate newer measurable ventilation metrics such as tidal volume.Additionally, we evaluated 1 characteristic of EtCO 2 over resuscitation.Other continuous capnography quality metrics such as airway opening index may be contributing to OHCA outcomes as well. 28

20 Survivors
End of resuscitationReturn of spontaneous circulation (ROSC) vs non-ROSC cases are shown in the top row.Survivors vs nonurvivors are shown in the bottom row.The center line in each box indicates the 50th percentile (median) of that category's EtCO 2 value.The bottom of each box indicates the 25th percentile, and the top of each box indicates the 75th percentile.The whisker below the box is the lower adjacent value (equal to the 25th percentile minus 1.5 times the IQR).